Porphyromonas gingivalis is considered to be one of the major etiologic agents of periodontal diseases. Studies assessing the host inflammatory response to P. gingivalis have demonstrated that the innate immune receptors, TLR2 and TLR4, are the major TLRs involved in the recognition of both the LPS and various pathogen associated molecular patterns isolated from P. gingivalis. However, as demonstrated from both in vitro and in vivo studies, TLR2 has been documented to be the predominant TLR involved in regulating the innate immune response to the whole bacterium of P. gingivalis. Studies have shown that the absence of TLR2 results in abrogated or suppressed host inflammation, enhanced bacterial clearance, and attenuated bone loss. Thus, the TLR2-mediated inflammatory response induced by P. gingivalis appears to be critical for its ability to exacerbate the disease process. Due to the primary importance of TLR2 in mediating the inflammatory response to whole-cell P. gingivalis, we focused on the intracellular signaling pathways activated by TLR2 and have subsequently identified that the Janus Kinase 2 (JAK2) plays an essential role in controlling the innate inflammatory response. Our specific hypothesis is that JAK2 is a central kinase controlling TLR2- mediated inflammation by P. gingivalis-stimulated innate immune cells and thus plays an essential role in the disease process. This hypothesis is based on: 1) stimulation of innate immune cells [human gingival epithelial cells (EC), dendritic cells (DC), and macrophages] with P. gingivalis resulted in the TLR2-dependent activation of JAK2, and inhibition of JAK2 attenuated the inflammatory response; (2) stimulation of innate immune cells with P. gingivalis resulted in the association of activated JAK2 with the cytosolic domain of TLR2; (3) immunoprecipitation of TLR2 from P. gingivalis-stimulated cells demonstrated the association of JAK members JAK2, JAK3, and TYK2 with TLR2; (4) inhibition of JAK2 resulted in the loss of P. gingivalis-mediated tyrosine phosphorylation of TLR2 and loss of JAK2, JAK3, and TYK2 recruitment to TLR2; (5) inhibition of JAK2 resulted in the abrogated activation of the NF-:B p65 signaling pathway; (6) JAK2 was activated in mice challenged with P. gingivalis; and (7) in vivo inhibition of JAK2 abrogated the host inflammatory response in mice challenged with P. gingivalis. These preliminary findings are the first to characterize a functional cell- signaling pathway for JAK2 in regulating TLR2-mediated innate immune responses, including how JAKs are activated and recruited to TLR2, and have identified that the ability of TLR2 to activate/recruit JAKs to TLR2 is a fundamental process involved in the inflammatory response to P. gingivalis. The Specific Aims will define the functional role the JAK2 pathway plays in regulating the host inflammatory response to P. gingivalis, and assess the importance of targeting JAK2 in vivo by determining how JAK2 inhibition affects the ability of P. gingivalis to induce host inflammation and bone loss in a mouse model.